1782-LB: Treatment Efficacy of Diabetic Kidney Disease with a Novel Specific Cathepsin L Inhibitor

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease (ESKD), yet there are no specific drugs for DKD. In previous research, we found that the lysosomal enzyme Cathepsin L (CTSL) is upregulated in diabetic patients, and high glucose levels can activate CTSL protein function (eLife, accepted). We also discovered the important role and mechanism of CTSL in COVID-19 infection (PMID: 33774649, 35668062). Previous studies have shown that CTSL activation can lead to podocyte fusion and detachment, resulting in proteinuria. Broad-spectrum cathepsin inhibitors protect renal function in animals and prevent proteinuria. However, current cathepsin inhibitors have non-specific targets and result in significant side effects, making them unsuitable for human use. Here, we developed a novel CTSL inhibitor (US Patent No: US11858905B1) that specifically targets CTSL without significant side effects. We confirmed in db/db mice (with early-stage DKD phenotype) and BKS-db-eNos^-/- mice (with late-stage DKD phenotype) that: 1. Acute administration for 3 days at a dose of 1000mg/kg showed no significant toxicity; chronic administration for 16 weeks at a dose of 20mg/kg showed no significant toxicity and reduced the mice’s water and food intake. 2. Chronic administration for 16 weeks improved markers of kidney damage in db/db mice and BKS-db-eNos^-/- mice, such as urine albumin creatine ratio, urine NGAL creatine ratio, and urine Kim-1 creatine ratio. 3. Pathological results showed a significant reduction in glomerular volume, renal interstitial inflammation, and PASM staining indicated a significant improvement in glomerular sclerosis with the use of the novel CTSL inhibitor. Masson staining suggested a significant improvement in renal interstitial fibrosis with the CTSL inhibitor. Our study demonstrates the significant improvement in diabetic kidney disease treatment with the novel CTSL inhibitor.